Neurons of the central nervous system (CNS) possess a number of cell surface receptors, each of which can be activated by a selective amino acid analogue. One of the most important of those receptors is the "NMDA" receptor, which takes its name from N-methyl-D-aspartate, an amino acid that stimulates the receptor. Since NMDA does not occur naturally in the brain, it is believed that amino acid neurotransmitters such as glutamate or aspartate probably stimulate NMDA receptors in vivo.
When glutamate or NMDA binds to the receptor complex, membrane pores (ion channels) open, allowing cations to diffuse through the channels, resulting in excitation of the cell. This process is essential for normal brain functions such as learning and appropriate control of motor activity. Excessive excitation at this receptor has been implicated in the rapid and irreversible damage of brain tissue which follows injury or deprivation of oxygen or energy sources. There is also evidence that the NMDA receptor complex may play a role in degenerative disorders such as Huntington's chorea and Alzheimer's disease, and in the etiology of epilepsy.
Therefore, pharmacologic control of such binding, which can come from an understanding of the specific receptor molecules and the subsequent biological processes involved, is a much sought after goal. Potentially, it should be possible to optimize `normal` learning, prevent certain degenerative disorders, assist in the rehabilitation of individuals who have been compromised by ischemic injury or degenerative diseases, and prevent or control certain types of epileptic seizures. Unfortunately, the study of the NMDA receptor and other amino acid specific receptors has been difficult because only crude preparations of brain cell membranes could be used as the source of receptors, and the structural basis for receptor activation is not completely understood.
It is known that the NMDA receptor complex in brain tissue has binding sites for drugs, excitatory neurotransmitters, modulating amino acid ligands, and cations. The consequences for nerve function depend on the interactions of the various ligands. The amino acid glycine potentiates NMDA receptor response through a glycine recognition site that is part of the NMDA receptor complex but is separate from the NMDA or glutamate binding site. Recently, Kemp, et al., reported that 7-chlorokynurenic acid is a selective antagonist of the glycine modulatory site. (Proc. Nat'l. Acad. Sci. USA 85:6547-6550, 1988). However, the receptor was neither characterized nor preferred by that group.
Glycine also serves as a neurotransmitter in the spinal cord, where it binds to a strychnine sensitive receptor. Although this binding site is functionally different from that found on the NMDA receptor complex, it too is physiologically very important. There is a corresponding need to isolate and study this receptor, which may be involved in spinal cord degeneration and seizures.
Therefore, a great need remains for compounds that can be used for isolation of such receptors and methods and reagents for facilitating receptor isolation.